We identified microRNA expression patterns associated with diagnosis, prognosis, and therapeutic outcome in colon adenocarcinoma. MircoRNAs associated with diagnosis and prognosis were first identified in a cohort recruited from the NCI-Maryland Colon Cancer Case-Control Study. These findings were validated in an independent cohort recruited from Hong Kong. This study was the largest to date profiling microRNA expression patterns in colon tumors and the only study to analyze associations with prognosis or therapeutic outcome. Thirty-seven microRNAs were differentially expressed in tumors. Five microRNAs were selected for validation by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). They were miR-20a, miR-21, miR-106a, miR-181b, and miR-203 and all were increased in tumors in the validation cohort. Higher miR-21 expression was also found in colon adenomas indicating altered expression of this mircoRNA may be an early event in colon carcinogenesis. We also found that tumors with high expression of miR-21 are associated with poor survival outcome and poor therapeutic outcome to adjuvant chemotherapy in both cohorts, independent of staging and other clinical covariates. Therefore, miR-21 expression is a strong candidate as a biomarker of diagnosis, prognosis, and therapeutic outcome of colon adenocarcinomas. Inflammatory genes and microRNAs have roles in colon carcinogenesis;therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined microRNA-21 expression. Quantitative RTPCR measured the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n=57) and this model was tested in both a test (n=56) and validation (n=83) cohort. Expression data for microRNA-21 was available for these patients and was compared to and combined with inflammatory gene expression. PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (Z score &gt;1.5) and were used to generate inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P=0.01) and validation (P=0.02) cohorts. This association was strong for stage II cases (P=0.002). microRNA-21 expression was associated with IL-6, IL-8, IL-10, IL-12a and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and microRNA-21 expression were independently associated with cancer-specific mortality, including stage II patients alone. IRS and microRNA-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high risk patients.